The Candidate, Kathryn A. Cunningham, has been supported by a K02 (DA00260) from 5/1/96-4/30/05, a period marked by a number of career, research and mentoring successes. The PI is the Chauncey Leake Distinguished Professor in Pharmacology at the University of Texas Medical Branch (UTMB), is the Director of the UTMB Center for Addiction Research and Director of a NIDA training grant. Continuously funded by NIDA, she has been active in drug abuse research for 20 years and has made important contributions to the field in areas related to both the neurobiology of abused drugs and addictive processes. Her current research endeavors are focused on gaining a more complete understanding of the neural basis underlying the effects of cocaine and the substituted amphetamine 3,4-methylenedioxymethamphetamine (MDMA) which share actions to stimulate brain serotonin (5-HT) systems. Serotonin is involved in the etiology of psychotic and affective disorders (e.g., anxiety, depression) which are often experienced by drug users and the 5-HT system is an important target in the quest for medications for addiction. Accordingly, the research goals of the present application for a K05 will include tests of the following hypotheses: (1) the oppositional roles of 5-HT2A receptors (5- HT2AR) and 5-HT2CR to control the cellular and behavioral responses to cocaine occur within the mesocorticoaccumbens circuit; models of addictive behavior (conditioned place preference, self-administration), high resolution immunohistochemistry and localized microinjection of receptor-specific ligands and virally-mediated genes are being employed [DA 06511]; (2) the in vivo effects of MDMA are mediated by both concurrent and sequential activation of 5- HT and dopamine systems; behavioral pharmacological and molecular biological tools are being used to dissect the roles of these systems [DA 13595]; (3) vulnerability to drug self-administration is related to the protein profile of the chronic stress response in brain; proteomics approaches are being employed to assess this hypothesis [DA 0 16905]. With the current proposal for a K05, these research goals will be supplemented by the development of expertise and the application of emerging proteomics technologies to characterize key proteins and protein signatures associated with exposure to abused drugs in animal models of addiction and in vulnerability to drug dependence. A related long term goal is to expand our program via collaborative interactions to include translational investigations in the identification of serum biomarkers of addiction phenotypes to allow detection of the disease at earliest stage of progression (diagnostic) and biomarkers of the disease stage in an addict to foretell disease and treatment outcome (prognostic). The mentoring goals will be to provide guidance for junior scientists in transdisciplinary investigations in addiction research, to continue to administer the NIDA training grant [DA07287] and to develop curricula for the training of health care professionals in the sciencebased treatment of drug dependence. The leadership goals include creation and direction of the University of Texas Medical Branch (UTMB) Center for Addiction Research, continued involvement in research initiatives in drug abuse at UTMB, in Texas and the U.S., and active participation in the leadership of the College on Problems of Drug Dependence.